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Abstract

Volume 12, Issue 3 (May 2010) 12, 336–343; 10.1038/aja.2010.5

Identifi cation of a novel germline missense mutation of the androgen receptor in African American men with familial prostate cancer

Si-Yi Hu1, Tao Liu1, Zhen-Zhen Liu1, Elisa Ledet2, Cruz Velasco-Gonzalez3, Diptasri M Mandal2 and Shahriar Koochekpour1,2,4

1 Stanley S Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
2 Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
3 School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
4 Department of Microbiology and Immunology, Department of Urology, Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA

Correspondence: Dr Shahriar Koochekpour,skooch@lsuhsc.edu

Received 19 November 2009; Revised 26 December 2009; Accepted 27 January 2010; Published online 22 February 2010.

Abstract

Race, family history and age are the unequivocally accepted risk factors for prostate cancer (PCa). Androgen receptor (AR)-dependent signaling is an important element in prostate carcinogenesis and its progression to metastatic disease. We examined the possibility of genomic changes in the AR in association with familial PCa in African Americans who have a higher incidence and mortality rate and a clinically more aggressive disease presentation than Caucasians. Genomic DNAs of 60 patients from 30 high-risk African American and Caucasian families participating in the Louisiana State University Health Sciences Center genetic linkage study of PCa were studied. Exon-specific polymerase-chain reaction, bi-directional automated sequencing and restriction enzyme genotyping were used to analyze for mutations in the coding region of the AR gene. We identified a germline AR (A1675T) (T559S) substitution mutation in the DNA-binding domain in three PCa-affected members of an African-American family with a history of early-onset disease. The present study describes the first AR germline mutation in an African-American family with a history of familial PCa. The AR (T559S) mutation may contribute to the disease by altering AR DNA-binding affinity and/or its response to androgens, non-androgenic steroids or anti-androgens. Additional studies will be required to define the frequency and contribution of the AR (A1675T) allele to early-onset and/or familial PCa in African Americans.

Keywords: African Americans; androgen receptor; familial prostate cancer; germline mutation

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